Effect of a Known P-glycoprotein (P-gp) Inhibitor, Itraconazole, on the Pharmacokinetics (PK) of Engasertib

A Phase 1, Open-label Study to Evaluate the Effect of a Known P-gp Inhibitor, Itraconazole, on the Pharmacokinetics of Engasertib in Healthy Adult Participants

The primary objective of this trial is to assess the effect of a known P-gp inhibitor, itraconazole, on the PK of engasertib in healthy adult participants.

Inclusion Criteria:

1. Age of 18 to 55 years (both inclusive), at the time of signing the informed consent.
2. Body weight ≥ 50 and < 120 kg and a body mass index (BMI) within the range 18 to 30 kg/m^2 (both inclusive) at screening.
3. Male and female participants are eligible to participate if they are not fertile or if they agree to either be abstinent from intercourse where pregnancy can occur or use contraception/barrier as detailed in the protocol.
4. Overtly healthy as determined by medical evaluation including medical history, physical examination, vital signs, electrocardiogram (ECG).
5. Clinically acceptable clinical laboratory test results at screening.
6. Non-smoker, former smoker or stable non-smoker (= 0 cigarettes, pipes, cigars, or others) for at least 3 months prior to screening. Participants must also have abstained from use of other nicotine containing products (e.g., nicotine patch, chewing gum or e-cigarettes) for at least 3 months before screening.
7. Capable of giving signed informed consent.
8. Re-admission: overtly healthy as determined by medical evaluation including check of changes in medical history compared to screening, clinical laboratory test results, abbreviated physical examination, vital signs, and ECG.

Exclusion Criteria:

1. Any history or evidence of any clinically relevant cardiovascular, hepatic, renal, gastrointestinal, pancreatic, endocrinologic, hematologic, immunologic, metabolic, and/or other major disease or malignancy as determined by medical evaluation (including physical examination) capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
2. Any clinically important illness, medical/surgical procedure, or condition, which, in the opinion of the investigator, is likely to interfere with the study conduct.
3. Known or suspected hypersensitivity to engasertib, or itraconazole, or any components of the formulation used.
4. History of significant or uncontrolled skin disorders, per the Investigator's judgement.
5. Any clinically significant history of allergic conditions (including allergies to more than 3 allergens, drug allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
6. History or presence of disorders of glucose metabolism.
7. Known or suspected thyroid disorders as evidenced by assessment of thyroid-stimulating hormone (TSH) levels outside the normal reference range at screening.
8. Known or suspected liver disorders (e.g., Morbus Gilbert / Meulengracht) and bile secretion/flow (cholestasis, also history of it).
9. Difficulty in swallowing.
10. History or evidence of malabsorption or any gastrointestinal surgery except appendectomy and herniotomy.
11. History of any chronic disease which might interfere with the absorption, distribution, metabolism or excretion of the study drug.
12. Lactose intolerance.
13. Contraindications for the use of itraconazole.
14. Tendency for vasovagal reactions (e.g., after venipuncture) or history of syncope.
15. Febrile illness within 1 week before first dosing.
16. Diagnosis or history of immunodeficiency or increased susceptibility to severe infection, or a clinically significant infection within 4 weeks prior to screening.
17. Use of any concomitant medication or any drugs / medicines (including dietary supplements, natural and herbal remedies, and hormone replacement therapy) within 2 weeks or 5 times the half-life of the respective drug, whichever is longer, prior to screening. Occasional use of paracetamol (2 grams/day; medicinal products in their original packaging, approved and marketed in Germany) is permitted. Oral, injectable, implantable, and topical contraceptives are permitted.
18. Administration of live, attenuated, replication-competent vaccine(s) and vector-based or mRNA COVID-19 vaccine(s) within 1 month prior to screening or plans to receive such vaccines during the study.
19. Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) within 3 months or 5 half-lives (whichever is longer) prior to screening.
20. Use of any investigational drug or participation in any clinical study within 30 days or 5 half-life times of study intervention administered in a previous trial, whichever is longer, prior to the expected date of first administration of study intervention or planning to take other investigational drugs during the study.
21. Positive for hepatitis B virus (HBV) panel test (Hepatitis B virus surface antigen [HBsAg], Hepatitis B Core Antibody [HBcAb], Hepatitis B surface antibody [HBsAb]), hepatitis C virus (HCV) (RNA), human immunodeficiency virus (HIV) 1+2 antibodies and HIV-1 p24 antigen combined at screening.
22. Positive screen for alcohol, drugs of abuse and cotinine test at screening.
23. Supine systolic blood pressure > 140 mmHg or < 90 mmHg; diastolic blood pressure > 90 mmHg or < 50 mmHg and pulse rate < 50 bpm or > 90 bpm (measurements taken after participant has been resting in supine position for 5 min), and tympanic body temperature of < 35.9 and > 37.6°C at screening.
24. 12-lead ECG with clinically relevant abnormality.
25. Elevations in alanine transaminase (ALT) > 1.1 x ULN, aspartate aminotransferase (AST) > 1.2 x ULN, serum bilirubin > 1.2 x ULN, creatinine ≥ 1.1 x ULN at screening.
26. Estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology Collaboration Creatinine Equation (2009) < 90 mL/min at screening.